Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline

Legro, Richard S.; Arslanian, Silva; Ehrmann, David A.; Hoeger, Kathleen M.; Murad, M. Hassan; Pasquali, Renato; Welt, Corrine K.

doi:10.1210/jc.2013-2350

Cited by 1,519 publications

(1,547 citation statements)

References 323 publications

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“…PCOS and normal ovarian tissue came from age-matched women, 38-40 y old. The diagnosis of PCOS was made according to National Institutes of Health (NIH) consensus guidelines (10,49), which include hyperandrogenemia, oligoovulation, polycystic ovaries, and the exclusion of 21-hydroxylase deficiency, Cushing's syndrome, and hyperprolactinemia. All of the PCOS theca cell preparations studied came from ovaries of women with fewer than six menses per year and elevated serum total testosterone or bioavailable testosterone levels (15,17,48).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

McAllister

Modi

Miller³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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191

157

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Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder. P olycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women world-wide (1). PCOS is associated with hyperandrogenemia/ hyperandrogenism, anovulation, infertility, and a characteristic ovarian morphology consisting of multiple small subcortical follicular "cysts" embedded in bilaterally enlarged ovaries (2-5). The presence of elevated circulating concentrations of testosterone results primarily from increased production of androgens by the ovaries, and is a classic endocrine phenotype of women with PCOS. Although there has been debate about the diagnostic criteria for PCOS, hyperandrogenemia/hyperandrogenism and anovulation, not explained by other causes, is a hallmark of the disorder, and is included as a key element in all "consensus" diagnosis schemes (6-10).There is consensus that the ovarian theca cells are the primary source of excess androgen biosynthesis in women with PCOS (11-13). Studies on freshly isolated thecal tissue or cultures of theca cells derived from normal and PCOS women have demonstrated that PCOS theca secretes greater amounts of androgen than theca tissue or cells from regularly ovulating women (12,(14)(15)(16)(17)(18)(19). Increased androgen biosynthesis in PCOS theca cells results from increased expression of the key enzymes involved in androgen biosynthesis, steroid-17-α-hydroxylase/17,20 lyase (encoded by the CYP17...

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Section: Methodsmentioning

confidence: 99%

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

McAllister

Modi

Miller³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

191

157

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“…Yet, as aforementioned, whether metformin is of benefit in treating PCOS remains unclear [37,38]. The majority of therapeutic studies have been small in size and have used metformin for a relatively brief period of time [33].…”

Section: Impact Of Metformin On the Clinical Features Of Pcosmentioning

confidence: 99%

“…Therefore, metformin is not recommended as a first-line treatment for management of menstrual irregularity or clinical hyperandrogenism in PCOS because of the lack of evidence for consistent benefits [37,38,44].…”

Section: Menstrual Irregularity and Clinical Hyperandrogenismmentioning

confidence: 99%

“…Similarly, in a more recent review consisting of 4227 women with PCOS, metformin only resulted in a marginal improvement in live birth rate when compared with placebo [45]. Therefore, metformin appears to have a limited role in improving fertility and live birth rate in women with PCOS and it is not recommended as a primary treatment for anovulatory infertility in this population [37,38].…”

Section: Menstrual Irregularity and Clinical Hyperandrogenismmentioning

confidence: 99%

“…Glucose tolerance Current guidelines for management of PCOS recommend metformin treatment for women with impaired glucose tolerance or type 2 diabetes who do not respond to lifestyle modification [37]. In type 2 diabetes, metformin is the recommended initial therapy and has also been demonstrated to reduce the risk of type 2 diabetes development in individuals with glucose intolerance [51].…”

Section: Impact Of Metformin On Metabolic Features Of Pcosmentioning

confidence: 99%

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Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome

Sam

Ehrmann

2017

Diabetologia

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Polycystic ovary syndrome (PCOS), the most common hormonal disorder among women of reproductive age, has various metabolic and reproductive consequences. Metformin was originally shown to lower testosterone levels in women with PCOS in the 1990s, an effect presumably related to its insulin sensitising actions. However, the precise mechanisms of metformin action in PCOS remain unclear and there is considerable heterogeneity in the clinical response to this therapy in women with PCOS. Recent evidence indicates that genetic factors may play a significant role in predicting response to metformin therapy in PCOS and future studies are needed to further identify women who are most likely to benefit from this therapy. At present, there is no clear evidence to support broad metformin use in PCOS. Well-designed prospective trials are needed to establish clear benefit for metformin use in the treatment of the reproductive and metabolic consequences associated with PCOS.

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Hormonal Evaluation of Hyperandrogenism in Women

Sam

Ehrmann

2015

JAMA

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Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline

Cited by 1,519 publications

References 323 publications

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome

Hormonal Evaluation of Hyperandrogenism in Women

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